Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

Fernández‐Majada, Vanesa; Aguilera, Cristina; Villanueva, Alberto; Vilardell, Felip; Robert‐Moreno, Alexandre; Aytés, Álvaro; Real, F.X.; Capellà, Gabriel; Mayo, Marty W.; Espinosa, Lluís; Bigas, Anna

doi:10.1073/pnas.0606476104

Cited by 124 publications

(118 citation statements)

References 47 publications

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“…6B). In line with this, BAY11-7082 was reported to block phosphorylation of the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) by IKKα (42,43). The alternative NF-κB pathway cooperates with CNK1 to foster cell invasion because downregulation of RelB by siRNA displays only a small effect on CNK1-knockdown cells (Fig.…”

Section: Discussionmentioning

confidence: 70%

CNK1 Promotes Invasion of Cancer Cells through NF-κB–Dependent Signaling

Fritz

Radziwill

2010

Molecular Cancer Research

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Hallmarks of cancer cells are uncontrolled proliferation, evasion of apoptosis, angiogenesis, cell invasion, and metastasis, which are driven by oncogenic activation of signaling pathways. Herein, we identify the scaffold protein CNK1 as a mediator of oncogenic signaling that promotes invasion in human breast cancer and cervical cancer cells. Downregulation of CNK1 diminishes the invasiveness of cancer cells and correlates with reduced expression of matrix metalloproteinase 9 (MMP-9) and membrane-type 1 MMP (MT1-MMP). Ectopic expression of CNK1 elevates MT1-MMP promoter activity in a NF-κB-dependent manner. Moreover, CNK1 cooperates with the NF-κB pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-κB pathway because knockdown of CNK1 interferes with processing of NF-κB2 p100 to p52 and its localization to the nucleus. In agreement with this, the invasion of CNK1-depleted cells is less sensitive to RelB downregulation compared with the invasion of control cells. Moreover, CNK1-dependent MT1-MMP promoter activation is blocked by RelB siRNA. Thus, CNK1 is an essential mediator of an oncogenic pathway involved in invasion of breast and cervical cancer cells and is therefore a putative target for cancer therapy. Mol Cancer Res; 8(3); 395-406. ©2010 AACR.

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Section: Discussionmentioning

confidence: 70%

CNK1 Promotes Invasion of Cancer Cells through NF-κB–Dependent Signaling

Fritz

Radziwill

2010

Molecular Cancer Research

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“…14 This mechanism operates not only in response to specific stimulation (such as laminin attachment) but also in cancer cells carrying activated IKKa. 22 By sequence analysis of the N-CoR protein, we have identified a putative IKK phosphorylation/14-3-3-binding site (RKS 2348 KSP) in the homologous region of the N-CoR protein (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Aberrant Cytoplasmic Localization of N-CoR in Colorectal Tumors

Fernández‐Majada

Pujadas²,

Vilardell³

et al. 2007

Cell Cycle

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“…Our data also indicate that both IKKa and IKKb enhance canonical CBF-1 activity in CaSki cells. This may be due to the mechanisms described by the Bigas group (Fernandez-Majada et al, 2007) and/or due to the upregulation of Notch ligands by NF-kB (Bash et al, 1999).…”

Section: Discussionmentioning

confidence: 99%